Age of mother and grandmother in relation to a subject's breast cancer risk.

BACKGROUND: On theoretical grounds, the age of the grandmother and the age of the mother at delivery of her daughter may affect the breast cancer risk of the granddaughter. METHODS: We used the data relating to the Diagnostic Research Mamma-carcinoma cohort (DOM (Diagnostisch Onderzoek Mammacarcinoom) 3), which comprises a population-based sample of 12 178 women aged 41-63 years at enrolment in 1982-85 and followed up until 2000. During follow-up 340 postmenopausal breast cancer cases were identified. To these we applied a case-cohort design together with a random sample from the baseline cohort (n=1826). Of these study participants, we were able to retrieve the birth dates of 998 mothers (309 cases, 689 controls), and for 547 of these we also retrieved the birth dates of the grandmothers (197 cases, 350 controls). A weighted Cox proportional hazards model was used to estimate the hazard ratios (HRs) for the effect of the age of the grandmother and the age of the mother on the breast cancer risk of the index women, while adjusting for potential confounders. RESULTS: Compared with the reference group aged 25-29.9 years, the group with the lowest maternal age (<25 years) had an age-adjusted HR of 0.77 (95% CI 0.19-3.12) and the group with the highest maternal age (> or = 40 years) had an age-adjusted HR of 1.58 (95% CI 0.01-267.81), P-value for trend=0.62. Compared with the same reference group, the group with the lowest grandmaternal age (<25 years) had an age-adjusted HR of 0.53 (95% CI 0.24-1.17) and the group with the highest grandmaternal age (> or = 40 years) had an age-adjusted HR of 7.29 (95% CI 1.20-44.46), P for trend=0.04. The associations did not change significantly after additional adjustment for various risk factors for breast cancer, neither for maternal age nor for grandmaternal age. CONCLUSION: This study does not suggest a major role of maternal age at delivery or grandmaternal age at delivery of the mother for the (grand)daughters' breast cancer risk.

Seasonal influences on hemoglobin levels and deferral rates in whole-blood and plasma donors.

BACKGROUND: Indications exist that deferral rates in blood donors are highest in summer. However, a detailed quantitative analysis is not available. The association between Hb values, deferral rates, and daily temperatures was investigated in a large data set of blood donors. STUDY DESIGN AND METHODS: The study population consisted of both plasma and whole-blood donors from the southeast region of the Netherlands. Individual Hb levels and other examination data between January 2002 and December 2004 were extracted from the donor file. Data on daily maximum temperatures were related to Hb levels and Hb deferrals. Results are reported separately for plasma and whole-blood donors as well as for men and women. RESULTS: Data were available from 106,398 whole blood donors and 6983 plasma donors, resulting in data of more than 600,000 examinations. Hb levels decreased with increasing daily temperature. Highest deferral rates were observed in summer months, which were consistent over the several groups and over the three years. The highest Hb deferral of 11.1 percent was observed for female whole-blood donors on days with a maximum temperature of 25 degrees and above. In all four donor categories a gradual increase with temperature was observed with 1.7-2.2 times higher deferral rates on hot days (> or = 25 degrees C) compared to cold days (<5 degrees C). CONCLUSION: A clear seasonal pattern in Hb levels and in the percentage of Hb deferrals was observed. The observed seasonal effect could not be explained by differences in donor characteristics. Our observations might have practical implications for donor management.

Reliability of biomarkers of iron status, blood lipids, oxidative stress, vitamin D, C-reactive protein and fructosamine in two Dutch cohorts.

Biomarkers are widely used in epidemiology, yet there are few reliability studies to assess the appropriateness of using these biomarkers for the assessment of exposure-disease relationships. The aim of the study was to assess the reliability of 20 biomarkers in serum collected from two Dutch centres (Utrecht and Bilthoven) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) at two points several years apart. Blood samples were collected from 30 men from Bilthoven and 35 women from Utrecht. Ferritin, total iron, total iron-binding capacity, transferrin saturation, transferrin, C-reactive protein, bilirubin, cholesterol, triglycerides, apo lipoprotein-A, apo lipoprotein-B, high-density lipoproteins, low-density lipoproteins, uric acid, creatinine, reactive oxygen metabolites, the ferric-reducing ability of plasma, protein thiol oxidation, fructosamine, and vitamin D biomarkers in serum were analysed from the blood samples at the two points of time. For all biomarkers, except C-reactive protein, there were no substantial changes in the mean levels over time. Uric acid, ferritin, creatinine, HDL, and apo lipoprotein-B levels consistently showed the highest reliability for men and women (intra-class correlation = 0.69-0.86). Among women, the ferric-reducing ability of plasma, and protein thiol oxidation had poor reliability; and among men iron-related biomarkers (except serum ferritin) had poor reliability. With the exception of a few gender-specific differences, most of the 20 biomarkers performed well and can be considered to have sufficient reliability to be used in future cohort studies.

Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women.

OBJECTIVE: To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. DESIGN: Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. RESULTS: Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m(2) or BMI>29.2 kg/m(2) compared to women with BMI within this range (P(heterogeneity)<0.0001, P(trend)=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P (trend)=0.005). CONCLUSIONS: Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.

Heritable aspects of dysplastic breast glandular tissue (DY).

Breast parenchymal patterns, as visible on mammograms, are determined by the relative amount of radio-dense, glandular dysplastic tissue DY). High percentages of DY are related to higher breast cancer risk. Previous studies reported heritable influences on DY of 32-67%, depending on the family relationship that was studied. depending on the family relationship that was studied. We assessed heritability in 466 sister-, 25 dizygotic twin- and 26 monozygotic twin-pairs participating in a population-based breast cancer screening program; the DOM project (Diagnostic Investigation Mamma Carcinoma). The heritability was estimated for non-twin sisters, dizygotic and monozygotic twins seperately by computing correlations between siblings from the dichotomous DY-score (high risk versus low risk). This was done using methods based on the number of shared genes per sibtype. Heritability estimates were 38, 34 and 88% for sisters, dizygotic twins and monozygotic twins respectively. Heritability estimates from models that combine monozygotic twins with dizygotic twins or sisters indicated that combine monozygotic twins with dizygotic twins or sisters indicated that dominant gene effects, genetic interactions or gene-environment effects could be involved. Parity appeared to have an effect on the heritabile influence with estimates ranging from 90% in sisters that were both nulliparous, to 2% in sisterpairs discordant for nulliparity. These result indicate a substantial genetic influence on DY, but with a possible modifying ability of other factors, such as parity.

Increase in breast size after menopause: prevalence and determinants.

OBJECTIVES: To determine the prevalence and determinants of increases in breast size after menopause. METHODS: Subjects were 1130 postmenopausal women, aged 54-71, participating in a population based breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Questionnaire data on changes in breast size, parity, age at first childbirth, breast feeding, age at menarche, age at menopause, HRT use and usual weight between age 30 years and age at questionnaire were used. Weight and height were measured at three screening rounds and waist and hip circumference was measured once. RESULTS: 18.6% of the women reported that they had to buy a larger bra because of changes in breast size, whereas 1.7% reported that they had to buy a smaller bra. Weight gain, waist circumference, hip circumference, Quetelet's index at third screening, Quetelet's index at first screening, waist-to-hip ratio and years since menopause were significantly associated with increased breast size (odds ratios between 2.5 and 1.4) (all tests for trend P < 0.05), whereas age at menopause, HRT use, parity and age at menarche were modestly, though not significantly associated with increased breast size. Age, usual Quetelet's index, age at first childbirth and number of months of full breast feeding were not associated with increased breast size. CONCLUSION: About one in five women experienced an increase in breast size after menopause. The most important factor associated with such an increase was found to be weight gain.

Urinary endogenous sex hormone levels in postmenopausal women after caloric restriction in young adulthood.

We investigated whether the 1944-1945 Dutch famine has affected postmenopausal sex hormone concentrations with data from 163 women (young adults during the famine). Urinary sex hormone concentrations showed modest elevations with increasing famine exposure. Effects were absent in parous women, but more pronounced in women who had never given birth.

Reproducibility over time of measurements of androgens, estrogens and hydroxy estrogens in urine samples from post-menopausal women.

Sex steroid concentrations in urine samples from post-menopausal women have been associated with risk of various chronic diseases. The basic requirement for the assessment of risk in such large-scale epidemiological studies is that subjects be ranked accurately by their average, long-term hormone levels. We examined the reproducibility over time of measurements of urinary testosterone (T), 5alpha-androstane-3alpha, 17beta-diol (ADIOL), estrone (E1), estradiol (E2), 2-hydroxy estrone and 2-hydroxy estradiol, (2(OH)-E), 16alpha-hydroxyestrone (16alpha(OH)-E1) and the ratio of 2(OH)-E and 16alpha(OH)-E1, in a representative sub-sample of post-menopausal women (n = 43) participating in an ongoing prospective cohort study. Women collected three first morning urine voids on different occasions, with average time difference between the first and the third urine sample of 5.1 years. T, ADIOL, E1 and E2 were measured by radio immunoassay after enzymatic hydrolysis, solid-phase extraction and HPLC purification of the samples, while 2(OH)-E and 16alpha(OH)-E1 were assayed by solid-phase enzyme immunoassay after enzymatic hydrolysis. Intra-class correlation co-efficients (ICCs) over time were very good for T (r = 0.85), acceptable for E2, E1 and ADIOL (r > 0.55), but low for 2(OH)-E, 16alpha(OH)-E1 and their ratio (r < 0.46). The adjustment for creatinine concentrations did not increase these correlations.

Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer.

To assess the relation between urinary endogenous sex steroid levels and the risk of postmenopausal breast cancer, a nested case-cohort study was conducted within a large cohort (the DOM cohort) in the Netherlands (n=9,349). Until the end of follow-up (1 January 1996), 397 postmenopausal breast cancer cases were identified and a subcohort of 424 women was then taken from all eligible women. Women using hormones were excluded, leaving 364 breast cancer cases and 382 women in the subcohort for the analyses. Concentrations of oestrone, oestradiol, testosterone, 5alpha-androstane-3alpha, 17beta-diol and creatinine were measured in first morning urine samples, which had been stored since enrolment at -20 degrees C. A Cox proportional Hazards model was used, with Barlow's adjustment for case-cohort sampling, to estimate breast cancer risk in quartiles of each of the, creatinine corrected, hormone levels, the lowest quartile being the reference group. Women with higher levels of all four of the hormones were at increased risk for postmenopausal breast cancer (highest vs lowest quartile: incidence rate ratio for oestrone (IRR(oestrone)=2.5, 95% CI: 1.6-3.8; IRR(oestradiol)=1.5, 95% CI: 1.0-2.3; IRR(testosterone)=1.6, 95% CI: 1.0-2.4; IRR(5alpha-androstane-3alpha, 17beta-diol)=1.7, 95% CI: 1.1-2.7). In conclusion, women with higher excretion levels of both oestrogens and androgens have an increased risk of breast cancer.

The role of genetic factors in age at natural menopause.

BACKGROUND: Environmental factors explain only a small part of the age variance at which menopause commences. The variation in natural menopause is a trait predominantly determined by interaction of multiple genes, whose identity and causative genetic variation remains to be determined. Menopause is a retrospective marker for the reproductive capacity of preceding years, since subfertility and infertility precede menopause at distinct time-intervals. In the present study we have investigated the contribution of genetic factors to menopausal age. METHODS: Data were collected from a random population sample of singleton and twin sisters participating in a prospective breast cancer screening project, who had subsequently experienced natural menopause. Heritability of menopausal age was estimated with analysis of variance, Mx modelling and Gibbs sampling. RESULTS: All produced almost identical heritability estimates of 0.85-0.87 for singleton sisters, suggesting a strong genetic contribution to menopausal age. Twin data were used to distinguish additive genetic from common environmental effects; a heritability of 0.71-0.72 was determined, which does not deviate significantly from the estimate for singleton sisters. CONCLUSIONS: According to our findings, a woman with a family history of early menopause risks early menopause and consequently early reproductive failure herself.

Oral contraceptive use in relation to age at menopause in the DOM cohort.

BACKGROUND: We investigated the hypothesis that long-term use of oral contraceptives (OCs), in particular high-dose OCs, could postpone age at menopause. METHODS: Data was used from 8701 women who participated in a breast cancer screening programme in Utrecht (DOM-3 cohort), and who did not use hormone replacement therapy (HRT) or OCs in the 4 years prior to their last menses. Data on OC-use, menopausal status, age at menopause, year of birth, parity, smoking behaviour, socio-economic status, body mass index and age at menarche was available. Use of high-dose OCs has been defined in this study as OC-use before 1972. The data was analysed by means of linear regression and Cox's proportional hazards analysis. Women still menstruating, women with surgical menopause and women lost to follow-up were censored at their last known date of menstruation. Endpoint was the natural menopause (n = 4589). RESULTS: The use of high-dose OCs advanced the onset of menopause by approximately 1.2 months for every year of OC-use compared with no OC-use. High-dose OC-use for > or = 3 years, adjusted for confounding variables, increased the risk of earlier menopause compared with no OC-use (adjusted hazard ratio 1.12; 95% CI 1.03--1.21). The use of lower dose OCs did not increase the risk of earlier menopause (adjusted hazard ratio 1.00; 95% CI 0.91--1.09). CONCLUSIONS: These results are inconsistent with the hypothesis that long-term use of OCs could postpone the onset of menopause by inhibiting follicle depletion. Possible explanations are discussed.

Prospect-EPIC Utrecht: study design and characteristics of the cohort population. European Prospective Investigation into Cancer and Nutrition.

The European Prospective Investigation into Cancer and Nutrition (EPIC), which has been established in order to investigate the relations between nutrition and cancer, was initiated in 1990 and involves 10 European countries with heterogeneous dietary patterns and differing cancer incidence rates. This manuscript presents the design, recruitment and baseline characteristics of the Prospect-EPIC cohort co-ordinated in Utrecht, The Netherlands. The cohort is based on volunteers recruited among women participating in a regional breast cancer screening program. It comprises of 17,357 subjects aged 50-69 years at enrolment from Utrecht and vicinity, who have consented to participate in the study and its follow-up. Each participant filled out a general questionnaire and a food frequency questionnaire. Participants were also physically examined and have donated a blood sample. Participation rate was 34.5%. Blood samples were donated by most participants (97.5%) and detailed informed consents were obtained from 87.4% of participants. Mean age at enrolment was 57 years. Anthropometric, lifestyle and morbidity characteristics of the cohort population did not differ largely from those of similar study populations in The Netherlands. Based on the Prospect-EPIC population, we intend to conduct prospective total cohort, nested case-control or case-cohort studies, in order to investigate relations between consumption of certain food groups or nutrients and chronic diseases, including hormone dependant cancers such as breast, colon, endometrial and ovary cancers.

Determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1-3 in premenopausal women: physical activity and anthropometry (Netherlands).

OBJECTIVE: Epidemiologic studies suggest that subjects with elevated plasma concentrations of insulin-like growth factor (IGF)-I are at increased risk of developing cancer. The objective of our study was to assess whether cancer risk factors such as lack of physical activity, obesity, and central body fat distribution are associated with plasma levels of IGF-I and related proteins (i.e. IGF binding proteins 1-3 and C-peptide). METHODS: A cross-sectional study was conducted in a population of 225 premenopausal women, aged 49-57, participating in the Prospect-EPIC study in the Netherlands. Plasma concentrations of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were determined. On the day of blood collection height, weight, and waist and hip circumference were measured. Habitual physical activity was assessed using a validated self-administered questionnaire. RESULTS: Mean concentrations of plasma IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were 156.1, 14.3, 434.4, 3062, and 2.86 ng/ml, respectively. Women in the highest tertile for physical activity had lower plasma concentrations of IGF-I, IGFBP-3, and C-peptide, and higher concentrations of IGFBP-1 and IGFBP-2, as compared to women in the lowest tertile. However, these differences were not statistically significant. BMI and related measures were significantly inversely associated with IGFBP-1 and IGFBP-2, and positively with IGFBP-3 and C-peptide. Linear regression analyses showed that the non-significant association of physical activity with components of the plasma IGF system was further attenuated by adjusting for obesity and central body fat distribution. CONCLUSIONS: Our data suggest that an active lifestyle is not independently associated with the plasma IGF system. We did confirm that a lean body shape is associated with higher concentrations of IGFBP-1 and IGFBP-2, and possibly also with lower concentrations of IGF-I and IGFBP-3.

Sequential analysis of matched dichotomous data from prospective case-control studies.

Sequential analysis of randomized controlled clinical trials and epidemiological prospective (matched) case-control studies can have ethical or economical advantages above a fixed sample size approach. It offers the possibility to stop early when enough evidence for an apparent effect of the risk factor or lack of the expected effect is achieved. In clinical trials it is well accepted to stop the trial early in favour of the alternative hypothesis. In epidemiological studies, in general, the need is not felt to stop early in case of a clear exposure effect. Little attention has been paid, however, to early stopping and accepting the null hypothesis. In metabolic epidemiological studies, where analysis destroys the biological material, the question of efficient use of samples, for example, those stored in a biobank, becomes crucial. Also a slow accrual of cases or the costs of follow-up of a cohort nested study can make it desirable to stop a study early once it becomes clear that no relevant exposure effect will be found. Matching can further reduce the amount of information necessary to reach a conclusion. We derived test statistics Z (efficient score) and V (Fisher's information) for the sequential analysis of studies with dichotomous data where each case can be matched to one or more controls. A variable matching ratio is allowed. These test statistics can be entered into the software PEST to monitor the course of the study. The double sequential probability ratio test and the double triangular test were evaluated with simulated data for odds ratios equal to 1.5, 2.0 and 2.5 and various type I and type II error probabilities both under H(0) and under H(1). Our simulations resulted in average and median values for the amount of information (V) that are far less than those for a fixed sample size study. Efficiency gain ranges from 32 per cent to 60 per cent. The proposed sequential analysis was applied in an investigation on the possible relationship between the polymorphism of the MTHFR-gene and rectal cancer in a cohort of women with cases matched by age to one and to three controls. A sequential analysis of matched data can lead to early stopping in favour of H(0) or H(1), thus conserving valuable resources for future testing. A sequentially designed study can be more economical and less arbitrary than a study that makes use of conditional power or conditional coverage probability calculations to decide early stopping.

Long-term oral contraceptive use increases breast cancer risk in women over 55 years of age: the DOM cohort.

The role of past oral contraceptive use in the development of breast cancer is unclear, particularly in postmenopausal women. The authors investigated this relationship among pre- and postmenopausal middle-aged women in a nested case-control study within the population-based DOM cohort, Utrecht, the Netherlands. Among a total population of 12,184 women followed up for an average of 7.5 years, 309 breast cancer cases aged 42 to 63 years, diagnosed from November 1982 through May 1996, and 610 controls were examined. Overall, duration of oral contraceptive use was not clearly related to breast cancer. In women older than 55 years, however, oral contraceptive use for more than 10 years was associated with a 2-fold increased risk of breast cancer (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.0). We conclude that long duration of oral contraceptive use increases the risk of breast cancer in women over 55 years of age but not in younger women.